OR33-5 S-Adenosylmethionine(SAM) Downregulates High Glucose Mediated Increase in TNF Expression in Human CD14+ Monocytes by Modulating Phosphodiesterase 4B

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR33-Insulin Signaling & Inflammation
Basic
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 303 (Moscone Center)
Leila Gobejishvili*, Diana Avila, Deepa Mokshagundam, Craig J McClain, Sri Prakash L Mokshagundam and Shirish S Barve
University of Louisville, Louisville, KY
Chronic systemic inflammation has been shown to be an important factor in the development of type 2 diabetes mellitus and its complications. Both animal and clinical work has shown that high glucose (HG) plays significant pathogenic role in sustained inflammation via increased expression of inflammatory cytokines and enhanced generation of reactive oxygen species. We have previously reported that HG exposed monocytes express higher levels of endotoxin inducible TNF which is mediated by enhanced expression of cAMP specific phosphodiesterase 4B (PDE4B). Work done by our group and others has shown that SAM supplementation can significantly attenuate LPS-induced TNF expression in monocytes/macrophages and Kupffer cells and this constitutes a major component of SAM’s ability to attenuate inflammation related organ injury.

In this study we examined whether SAM supplementation affects HG mediated increase in TNF expression.

We used human CD14+ monocytes from healthy individuals and cultured them with normal (5.5mM) and high (25mM) glucose concentrations, with or without lipopolysaccharide (LPS, 100 ng/ml) in the presence or absence of SAM (0.25 to 0.75 mM). Effect of SAM on HG and LPS responsive TNFα and PDE4B mRNA and protein expression was assessed by real time PCR and ELISA. Histone modifications at the TNFα and PDE4B promoter regions were analyzed to determine potential role of epigenetic mechanisms in modulating cytokine responses.

The results obtained demonstrate that SAM significantly lowered high glucose and LPS-inducible PDE4B and consequently decreased TNFa expression. This phenomenon was the result of epigenetic changes involving histone modifications at the PDE4B and TNFα promoters leading to alterations in the relevant transcription factor binding (CREB and NFκB). These data identify PDE4 expression as a significant pathogenic component of high glucose and endotoxin mediated inflammation which can be targeted by SAM for the potential therapeutic use in the treatment of diseases characterized by elevated TNFa expression.

Nothing to Disclose: LG, DA, DM, CJM, SPLM, SSB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by NIH grants AA014371, AA015970, and Office of Dietary Supplements